It is known in the pharmaceutical industry that the rate of dissolution of a particulate drug can increase with increasing surface area (e.g., by decreasing particle size). This increase can result in enhanced bioavailability of the particulate drug. In sustained release compositions where a drug particle is dispersed within a matrix, for example, a polymer matrix, improvements in release profiles are typically seen as a result of a reduction in the particle size of the dispersed drug. Therefore, it is often desirable to minimize and control the particle size of a drug.
The present invention relates to a sustained release composition comprising micron particles of a labile agent and a method of preparing and administering the sustained release composition. The invention further relates to micron particles of labile agent and a method of preparing the micron particles. The micron particles have a volume median particle size of less than about 2 microns. In a preferred embodiment, the particles are submicron particles having a volume median particle size of less than 1 micron.
The method of the invention for preparing a composition for the sustained release of a labile agent, comprises the steps of:
a) forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;
b) wet milling the suspension to achieve micron particles of the labile agent; and
c) removing the polymer solvent thereby forming a solid polymer/labile agent matrix.
The method can further comprise the step of forming droplets of the milled suspension prior to removal of the polymer solvent. Further, the method can comprise freezing the droplets prior to removal of the polymer solvent. According to the method of the invention, the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the polymer solvent can be removed by an evaporation and/or extraction process. In a preferred embodiment, the micron particles of labile agent are submicron in size.
The composition for sustained release of a labile agent is likewise prepared according to the method of the invention as described above. In other words, the composition for the sustained release of a labile agent as described herein is a composition prepared by the method comprising the steps of:
a) forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;
b) wet milling the suspension to achieve micron particles of the labile agent; and
c) removing the polymer solvent thereby forming a solid polymer/labile agent matrix.
The method for preparing micron particles of a labile agent comprises the step of (a) forming a suspension comprising the labile agent, dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent; and (b) wet milling the suspension. In a preferred embodiment, the particles of labile agent are submicron particles.
The micron particles of labile agent, as described herein, are prepared according to the method of the invention. Consequently, the micron particles of labile agent are prepared by forming a suspension comprising the labile agent, dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent, and wet milling the suspension.
The method described herein as compared to other known methods of particle size reduction, provides micron particles of proteins, peptides and oligonucleotides without agglomeration of the particles and with retention of biological activity. As shown in Example 1, known methods of particle size reduction such as sonication, are capable of achieving particles having a size of approximately 3 microns. However, achieving a particle size of about 2 microns or less without degradation of the labile agent can be readily achieved using the method described herein.
Importantly, the micron particles of labile agent once formed can, without isolation, be further processed to prepare a composition for the sustained release of labile agent. In addition, the sustained release compositions, which are prepared according to the claimed method, exhibit lower initial release of labile agent as a result of the micron particle size which they possess, thereby providing increased therapeutic benefits resulting from low peak serum concentrations and/or longer sustained duration.